In April, University of North Carolina at Chapel Hill researchers reported discovering how misshapen red blood cells could stick to capillary walls as they block blood flow and cause excruciating crises in patients with sickle cell disease. Now, they have made another, possibly more important discovery -- that a protein called thrombospondin in the blood largely controls, or activates, that sticking process.

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Now, they have made another, possibly more important discovery -- that a protein called thrombospondin in the blood largely controls, or activates, that sticking process. "This is incredibly exciting to us because it represents a whole new way of thinking about sickle cell adhesion," said Dr. Julia E. Brittain, postdoctoral fellow in pharmacology at UNC. "Our new work suggests it should be possible to improve treatment for the inherited disorder by finding one or more compounds that will neutralize the protein, something we have already done in the laboratory."

Sickle cell disease, also called sickle cell anemia, is the most common lethal genetic illness among blacks in the United States. About 150 in every 100,000 black children and young adults suffer from it, according to the American Medical Association.

A report on the experiments, funded by the National Institutes of Health, appears in the June 15 issue of the Journal of Clinical Investigation. Besides Brittain, authors, all at the UNC School of Medicine, are medical student Kathryn J. Mlinar of the Distinguished Medical Scholars Program; technician Christopher S. Anderson; Dr. Eugene P. Orringer, professor of medicine; and Dr. Leslie V. Parise, professor of the department of pharmacology.

"Before, circulating red blood cells were largely considered passive and were not thought to control anything by molecular signals, but it turns out that they definitely do," Brittain said. In the past, scientists believed that the misshapen cells, which look like red hooks or crescent moons under the microscope, clogged blood vessels because of their stiffness and odd shape. Healthy red cells look like ring-shaped life preservers and are somewhat pliable.

In the group's experiments, Brittain, working under Parise's direction, used a system that mimics blood flow and shear conditions inside blood vessels, as well as other characteristics such as temperature and flow rate. They found thrombospondin binds to affected red blood cells and causes the cells to create molecular signals that make those cells stick more readily to blood vessel walls.

The protein works by activating a receptor on the surface of red cells called integrin-associated protein, or IAP, said Parise, a member of both UNC's Center for Thrombosis and Hemostasis and Lineberger Comprehensive Cancer Center.

"Knowing that sickled cells can respond to elements in the blood and send signals to become more adhesive means that when we understand these signaling pathways better, we should be able to target them with drugs to decrease the adhesiveness," she said.

In further experiments, the scientists found that several compounds, including two enzyme inhibitors, prevented defective cells from sticking to vessel walls, Parise said.

Blocking IAP's action might become the key to preventing much of the microscopic logjam of defective red blood cells in capillaries and the resulting pain and tissue damage, Brittain said. Another promising approach would be to use special drugs to interrupt the molecular signaling mechanism in red cells that increases their stickiness.

Comparable signaling is known to occur in other kinds of cells, but has been overlooked in sickled cells, she said.

"It's reasonable to think this work could lead to improved lives for people with sickle cell disease," Brittain said. "That's our goal and our strong hope."

About one in 12 blacks has sickle cell trait, which means they carry a gene that produces a defective kind of hemoglobin, the complex protein that carries oxygen to tissues throughout the body, according to the AMA. When a person inherits the gene from a parent, he or she is a carrier like the parent but usually is symptom free. When two carriers have a child, there is a 25 percent chance the child will have sickle cell disease, 50 percent chance the child will be a carrier and a 25 percent chance he or she will have neither.

Until about 1960, most infants born with the illness died in childhood, but today with improved treatments many survive into adulthood. A relatively simple blood test can show who carries the sickle cell gene, and doctors advise that couples who both carry it should undergo genetic counseling before starting a family.

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